Carbohydrate metabolism

CARBOHYDRATE METABOLISM

By :-SANA DANISHSUBAS IMTIAZ NAJAF BATOOL

1

2015/1/3

2015/1/3

UOL PHARMACIST

2015/1/3

UOL

CONTENTS• Introduction

- Nutrition

- Carbohydrates

- Classification of carbohydrates

- Functions of carbohydrates

- What is metabolism?

• Major metabolic pathways of carbohydrates

- Introduction about each pathway

- Step of reactions in every metabolic pathway

- Clinical Aspects 5

• Polysaccharides and clinical aspects

• Role of hormones in carbohydrate metabolism

• Dental aspects of carbohydrate metabolism

• Recent issue related to carbohydrate metabolism

• Summary of carbohydrate metabolism

• Conclusion6

INTRODUCTION

7

NUTRITION

• Nutrition is defined as “ the science of how the

body utilizes food to meet requirements for

development growth, repair and maintenance.”

CARBOHYDRATES

FATS

PROTEINS

VITAMINS

MINERALS

WATER8

Daily Intake

• Nutrient Quantity Per Day

Energy = 8,700 kilojoules

Protein = 50 grams

Fat = 70 grams

Carbohydrates = 310 grams

Sugars = 90 grams

Sodium (salt) = 2.3 grams

Dietary Fibre = 30 grams

Saturated Fatty Acids = 24 grams

9

CARBOHYDRATE:

Most abundant organic molecule on earth.

Carbohydrates are defined as aldehyde or keto derivatives

of polyhydric alcohols.

For example: Glycerol on oxidation is converted to

D-glyceraldehyde, which is a carbohydrate derived from the

trihydric alcohol (glycerol).

All carbohydrates have the general formula CnH2nOn [or it

can be re-written as Cn(H2O)n ] .

10

CLASSIFICATION OF CARBOHYDRATE

CARBOHYDRATE

MonosaccharidesErythrose ,

Ribose,Glucose

Disaccharides

Oligosaccharides

Polysaccharides Starch , cellulose, dextrin , dextran

Sucrose , lactose

Maltotriose

11

FUNCTIONS OF CARBOHYDRATES

Main source of energy in the body. Energy

production from carbohydrates will be 4 k

calories/g (16 k Joules/g).

Storage form of energy (starch and glycogen).

Excess carbohydrate is converted to fat.

Glycoproteins and glycolipids are components of

cell membranes and receptors.

Structural basis of many organisms. For example,

cellulose of plants,exoskeleton of insects etc.

12

Biomedical Importance Of Glucose

• Glucose is a major carbohydrate

• It is a major fuel of tissues

• It is converted into other carbohydrates

Glycogen for storage.

Ribose in nucleic acids.

Galactose in lactose of milk.

They form glycoproteins & proteoglycans

They are present in some lipoproteins (LDL) .

Present in plasma membrane:glycocalyx.

Glycophorin is a major intergral membrane glycoprotein

of human erythrocytes.

13

Metabolism

Thousands of chemical reactions are

taking place inside a cell in an

organized, well co-ordinated and

purposeful manner; all these

reactions are called as

METABOLISM.

TYPES OF METABOLIC

PATHWAY:

Catabolic Pathway

Anabolic Pathway

Amphibolic Pathway

STAGES AND PHASES

OF METABOLISM:

Primary

Secondary

Tertiary14

Food molecules Simpler molecules

Amphibolic pathway

Anabolic Catabolic

Proteins, carbohydrates, CO2+H2O

lipids, nucleic acids etc.

15

Major Pathways of

Carbohydrate Metabolism

16

1) Glycolysis

2) Citric Acid Cycle

3) Gluconeogenesis

4) Glycogenesis

5) Glycogenolysis

6) Hexose monophosphate shunt

7) Uronic Acid Pathway

8) Galactose Metabolism

9) Fructose Metabolism

10) Amino sugar metabolism17

Entry of Glucose into cells1) Insulin-independent transport system of glucose:

Not dependent on hormone insulin. This is operative

in – hepatocytes, erythrocytes (GLUT-1) and brain.

2) Insulin-dependent transport system: Muscles and

adipose tissue (GLUT-4).

18

GlycolysisEmbden-Meyerhof pathway

(or)

E.M.Pathway

Definition:

Glycolysis is defined as the sequence of

reactions converting glucose (or glycogen) to

pyruvate or lactate, with the production of ATP

19

Salient features:

1) Takes place in all cells of the body.

2) Enzymes present in “cytosomal fraction” of the

cell.

3) Lactate – end product – anaerobic condition.

4) Pyruvate(finally oxidized to CO2 & H2O) – end

product of aerobic condition.

5) Tissues lacking mitochondria – major pathway –

ATP synthesis.

6) Very essential for brain – dependent on glucose for

energy.

7) Central metabolic pathway

8) Reversal of glycolysis – results in gluconeogenesis.20

Reactions of Glycolysis

1) Energy Investment phase (or) priming phase

2) Splitting phase

3) Energy generation phase

21

Energy Investment

Phase

• Glucose is phosphorylated to glucose-6-phosphate by hexokinase (or) glucokinase.

• Glucose-6-phosphate undergoes isomerization to give fructose -6- phosphate in the presense of phospho-hexose isomerase and Mg2+

• Fructose-6-phosphate is phoshorylated to fructose 1,6-bisphosphate by phosphofructokinase.

Splitting Phase

• Fructose 1,6-bisphosphate glyceraldehyde 3-phosphate + dihydroxyacetone phosphate.(aldolase enzyme)

• 2 molecules of glyceraldehyde 3-phosphate are obtained from 1 molecule of glucose

Energy Generation

Phase

• Glyceraldehyde 3-phosphate 1,3-bisphosphoglycerate(glyceraldehyde 3-phosphate hydrogenase )

• 1,3-bisphosphoglycerate 3-phosphoglycerate (phosphoglycerate kinase)

• 3-phosphoglycerate 2-phosphoglycerate (phosphoglycerate mutase)

• 2-phosphoglycerate phosphoenol pyruvate (enolase + Mg2+ & Mn2+)

• Phosphoenol pyruvate pyruvate [enol] (pyruvate kinase ) pyruvate [keto] L-Lactate (lactate dehydrogenase)

22

23

24

Energy production of glycolysis:

Net energy ATP utilized ATP produced

2 ATP 2ATP

From glucose to glucose -

6-p.

From fructose -6-p to

fructose 1,6 p.

4 ATP

(Substrate level

phosphorylation)

2ATP from 1,3 DPG.

2ATP from phosphoenol

pyruvate

In absence of oxygen

(anaerobic glycolysis)

8 ATP /

6 ATP (Pyruvate

dehydrogenase

2NADH,ETC,

Oxidative

phosphorylation)

2ATP

-From glucose to glucose -

6-p.

From fructose -6-p to

fructose 1,6 p.

4 ATP

(substrate level

phosphorylation)

2ATP from 1,3 BPG.

2ATP from phosphoenol

pyruvate.

+ 4ATP or 6ATP

(from oxidation of 2

NADH + H in

mitochondria).

In presence of oxygen

(aerobic glycolysis)

ATP production = ATP produced - ATP utilized

25

CLINICAL ASPECT

1) Lactic acidosis

- Normal value – 4 to 15 mg/dl.

- Mild forms – strenous exercise, shock,

respiratory diseases, cancers

- Severe forms – Impairment/collapse of

circulatory system – myocardial infarction,

pulmonary embolism, uncontrolled

hemmorrhage and severe shock.

26

2) Cancer and glycolysis :

- Cancer cells – increased uptake of glucose and glycolysis.

- Blood vessels unable to supply adequate oxygen – HYPOXIC condition – Anaerobic glycolysis / hypoxic glycolysis – Involvement of Hypoxic inducible transcription factor (HIF).

- Treatment : Use drugs that inhibit vascularization of tumours

27

Pasteur effect : Inhibition of glycolysis by

oxygen (Phosphofructokinase) .

Crabtree effect : The phenomenon of

inhibition of oxygen consumption by the

addition of glucose to tissues having high

aerobic glycolysis.

28

RAPARPORT – LEUBERING CYCLE

• Supplementary pathway/ Shunt pathway to glycolysis .

• Erythrocytes

• Synthesis of 2,3-bisphosphoglycerate (2,3-BPG).

• Without the synthesis of ATP.

• Help to dissipate or waste the energy not needed by RBCs.

• Supply more oxygen to the tissues.

29

CITRIC ACID CYCLEKREBS CYCLE / TRICARBOXYLIC ACID/

TCA CYCLE

Essentially involves the oxidation of acetyl CoA

to CO2 and H2O.

This Cycle utilizes about two-third of total

oxygen consumed by the body.

30

Brief History:

• Hans Adolf Krebs

• 1937

• Studies of oxygen consumptiom in pigeon breast muscle.

Location of TCA

• Mitochondrial matrix

• In close proximity to the electronic transport chain.

Overview

• 65-70% of the ATP is synthesized

• Name : TCA used because at the ouset of the cycle tricarboxylic acids participate.

31

Reactions of citric acid cycle

1) Formation of citrate : Condensation of acetyl CoA and

oxaloacetate catalysed by citrate synthase.

2) & 3) Citrate is isomerized to isocitrate aconitase (two

steps).

4) & 5) Formation of ᾀ-ketoglutarate : enzyme isocitrate

dehydrogenase.

6) Conversion of ᾀ-ketoglutarate to succinyl CoA :

through oxidative decarboxylation, catalysed by ᾀ-

ketoglutarate dehydrogenase complex.32

33

7)Formation of succinate : enzyme succinate thiokinase

GTP + ADP ATP + GDP (nucleoside diphosphate kinase)

8)Conversion of succinate to fumarase : enzyme succinate dehydrogenase

9)Formation of malate : enzyme fumarase

10)Conversion of malate to oxaloacetate : enzyme malate dehydrogenase.

33

34

• TCA cycle is strictly aerobic in contrast to glycolysis.

• Total of 12 ATP are produced from one acetyl CoA :-

During the process of oxidation of acetyl CoA via

citric acid cycle 3 NADH & 1 FADH2.

Oxidation of 3 NADH by electron transport chain

coupled with oxidative phosphorylation results in 9

ATP, FADH2 2 ATP.

One substrate level phosphorylation.35

Mitochondrial encephalopathy occurs due to fumarase deficiency .

It is a mitochondrial myopathy affecting both the skeletal muscles and brain .

APPLIED ASPECTS OF

TCA CYCLE

36

GLUCONEOGENESIS

The synthesis of glucose from non-carbohydrate compounds is known as gluconeogenesis.

Major substrate/precursors : lactate, pyruvate, glycogenic amino acids, propionate & glycerol.

-Takes place in liver (1kg glucose) ; kidney matrix( 1/3rd).

- Occurs in cytosol and some produced in mitochondria.

37

Importance of Gluconeogenesis

Brain,CNS,

erythrocytes,testes and kidney medulla dependent on glucose for cont. supply of energy.

Under anaerobic condition, glucose

is the only source to supply skeletal

muscles.

Occurs to meet the basal req of the

body for glucose in fasting for even

more than a day.

Effectively clears,certain metabolites

produced in the tissues that

accumulates in blood

38

Reaction of Gluconeogenesis

Glucose

39

Cori Cycle

40

Glucose-Alanine Cycle

41

Clinical Aspects

* Glucagon stimulates gluconeogenesis:

1)Active pyruvate kinase converted to inactive form

2)Reduces the concentration of fructose 2,6-bisphosphate.

* Glycogenic amino acids have stimulating influence on gluconeogenesis.

* Diabetes mellitus where amino acids are mobilized from muscle protein for the purpose of gluconeogenesis.

Acetyl CoA promotes gluconeogenesis:

* During starvation – due to excessive lipolysis in adipose tissue –acetyl CoA accumulates in the liver.

* Acetyl CoA allosterically activates pyruvate carboxylase resulting in enhanced glucose production

* Alcohol inhibits gluconeogenesis

42

GLYCOGEN METABOLISM

Glycogen is a storage form of glucose in animals.

Stored mostly in liver (6-8%) and muscle (1-2%)

Due to muscle mass the quantity of glycogen in muscle = 250g

and liver =75g

Stored as granules in the cytosol.

Functions : Liver glycogen – maintain the blood glucose level

Muscle glycogen – serves as fuel reserve

43

GLYCOGENESIS

Synthesis of glycogen from glucose.

Takes place in cytosol.

Requires UTP and ATP besides glucose.

Steps in synthesis :

1) Synthesis of UDP- glucose

2) Requirement of primer to initiate glycogenesis

3) Glycogen synthesis by glycogen synthase

4) Formation of branches in glycogen

44

45

GLYCOGENOLYSIS

Degradation of stored glycogen in liver and muscle constitutes

glycogenolysis.

Irreversible pathway takes place in cytosol.

Hormonal effect on glycogen metabolism :

1) Elevated glucagon – increases glycogen degradation

2) Elevated insulin – increases glycogen synthesis

Degraded by breaking majorly α-1,4- and α-1,6-glycosidic bonds.

Steps in glycogenolysis:

1) Action of glycogen phosphorylase

2) Action of debranching enzyme

3) Formation of glucose-6-phosphate and glucose

46

47

TYPE ENZYME DEFECT CLINICAL FEATURES

Type I (Von Gierke’s

disease)

Glucose-6-

phosphatase

deficiency.

Hypoglycemia, enlarged liver and kidneys,

gastro-intestinal symptoms, Nose bleed,

short stature, gout

Type II (Pompe’s

disease)

Acid maltase

deficiency

Diminished muscle tone, heart failure,

enlarged tongue

Type III (Cori’s

disease,Forbe disease)

Debranching

enzyme deficiency

Hypoglycemia, enlarged liver, cirrhosis,

muscle weakness, cardiac involvement

Type IV (Andersen’s

disease)

Branching enzyme

deficiency

Enlarged liver & spleen, cirrhosis,

diminished muscle tone, possible nervous

system involvement

Type V (Mcardle’s

disease)

Muscle

phosphorylase

deficiency

Muscle weakness, fatigue and muscle

cramps

Glycogen storage diseases

48

TYPE ENZYME DEFECT CLINICAL FEATURES

Type VI (Her’s

disease)

Liver phosphorylase

deficiency

Mild hypoglycemia, enlarged liver, short

stature in childhood

Type VII (Tarui’s

disease) Phosphofructokinas

e deficiency

Muscle pain, weakness and decreased

endurance

Type VIII Liver phosphorylase

kinase

Mild hypoglycemia, enlarged liver, short

stature in childhood, possible muscle

weakness and cramps

Type 0 Liver glycogen

synthetase

Hypoglycemia, possible liver enlargement

49

Von Gierke’s disease)

Pompe’s disease

50

Cori’s disease, Forbe

disease

51

HEXOSE MONOPHOSPHATE SHUNT

HMP Shunt/ Pentose Phosphate Pathway/

Phosphogluconate Pathway

52

* This is an alternative pathway to glycolysis and TCA cycle for the oxidation of glucose.

* Anabolic in nature, since it is concerned with the biosynthesis of NADPH and pentoses.

* Unique multifunctional pathway

* Enzymes located – cytosol

* Tissues active – liver, adipose tissue, adrenal gland, erythrocytes, testes and lactating mammary gland.53

Reactions of the HMP Shunt Pathway

54

• Pentose or its derivatives are useful for the synthesis of nucleic acids and nucleotides.

• NADPH is required :

- For reductive biosynthesis of fatty acids and steroids.

- For the synthesis of certain amino acids.

- Anti-oxidant reaction

- Hydroxylation reaction– detoxification of drugs.

- Phagocytosis

- Preserve the integrity of RBC membrane.

Significance of HMP Shunt

55

• Glucose-6-Phosphate dehydrogenase

deficiency :

- Inherited sex-linked trait

- Red blood cells

- Impaired synthesis of NADPH

- hemolysis , developing hemolytic anemia

Resistance towards malaria [Africans]

Clinical Aspects

56

Clinical Aspects

• Wernicke-Korsakoff syndrome :

- Genetic disorder

- Alteration in transketolase activity

- Symptoms : mental disorder, loss of memory,

partial paralysis

• Pernicious anemia : transketolase activity

increases.

57

URONIC ACID PATHWAY

(Or)

Glucoronic acis pathway

58

Alternative oxidative pathway for glucose.

synthesis of glucorinc acid,pentoses and vitamin (ascorbic acid).

Normal carbohydrate metabolism ,phosphate esters are involved – but in uronic acid pathway free sugars and sugar acids are involved.

Steps of reactions :

1) Formation of UDP-glucoronate

2) Conversion of UDP- glucoronate to L-gulonate

3) Synthesis of ascorbic acid in some animals

4) Oxidation of L-gulonate59

60

Clinical Aspects

• Effects of drugs : increases the pathway to achieve more synthesis of glucaronate from glucose .

- barbital,chloro-butanol etc.

• Essential pentosuria : deficiency of xylitol-dehydrogenase

- Rare genetic disorder

- Asymptomatic

- Excrete large amount of L-xylulose in urine

- No ill-effects61

METABOLISM OF GALACTOSE

62

63

METABOLISM OF FRUCTOSE

64

METABOLISM OF AMINO SUGARS

65

Electron transport chain reactions

• Electron transport chain is a series of protein

complexes located in the inner membrane of

mitochondria .

66

POLYSACCHARIDES&

CLINICAL ASPECTS

67

Proteoglycans & Glycosaminoglycans

Seven glycosaminoglycans :

1 ) Hyaluronic acid

2 ) Chondriotin sulfate

3 ) Keratan sulfate I

4 ) Keratan sulfate II

5 ) Heparin

6 ) Heparan sulfate

7 ) Dermatan sulfate

68

• Structural components of extracellular matrix.

• Act as sieves in extracellular matrix.

• Facilitate cell migration.

• Corneal transparency.

• Anticoagulant (Heparin).

• Components of synaptic & other vesicles.

Functions of glycoaminoglycans

69

MPS Defect Symptoms

MPS I (Hurler

syndrome)

Alpha-L-Iduronidase Mental retardation, micrognathia, coarse

facial features, macroglossia, retinal

degeneration,

corneal clouding, cardiomyopathy,

hepatosplenomegaly

MPS II (Hunter

syndrome)

Iduronate sulfatase Mental retardation (similar, but milder,

symptoms to MPS I). This type

exceptionally has X-linked

recessive inheritance

MPS IIIA

(Sanfilippo A)

Heparan sulfate N

sulfatase

Developmental delay, severe hyperactivity,

spasticity, motor dysfunction, death by the

second decade

MPS IIIB

(Sanfilippo B)

Alpha-

Acetylglucosaminidase

MPS IIIC

(Sanfilippo C)

Acetyl transferase

Mucopolysaccharidoses

70

MPS Defect Symptoms

MPS IVA

(Morquio A)

Galactose-6-sulfatase

Severe skeletal dysplasia, short stature,

motor dysfunctionMPS IVB (Morquio

B)

Beta galactosidase

MPS VI

(Maroteaux Lamy

syndrome)

N acetylgalactosamine 4

sulfatase

Severe skeletal dysplasia, short stature,

motor dysfunction, kyphosis, heart defects

MPS VII (Sly) Beta glucoronidase Hepatomegaly, skeletal dysplasia, short

stature, corneal clouding, developmental

delay

MPS IX (Natowicz

syndrome)

Hyaluronidase deficiency Nodular soft-tissue masses around joints,

episodes of painful swelling of the masses,

short-term pain, mild facial changes, short

stature, normal joint movement, normal

intelligence 71

Hunter’s syndrome

72

ROLE OF HORMONES IN CARBOHYDRATE METABOLISM

73

• Postabsorptive state: Blood glucose is 4.5-

5.5mmol/L.

• After carbohydrate meal: 6.5-7.2mmol/L

• During fasting : 3.3-3.9mmol/L

Regulation of Blood glucose

74

Metabolic & hormonal mechanisms

regulate blood glucose level

Maintenance of stable levels of glucose in blood is by

Liver.

Extrahepatic tissues.

Hormones .

75

Regulation of blood glucose levels

Insulin

76

Role of glucagon

77

Role of thyroid hormone

It stimulates glycogenolysis & gluconeogenesis.

Hypothyroid

Fasting blood glucose

is lowered.

Patients have

decreased ability to

utilise glucose.

Patients are less

sensitive to insulin

than normal or

hyperthyroid

patients.

Hyperthyroid

Fasting blood

glucose is elevated

Patients utilise

glucose at normal

or increased rate

78

Glucocorticoids

Glucocorticoids are antagonistic to insulin.

Inhibit the utilisation of glucose in extrahepatic tissues.

Increased gluconeogenesis .

79

Epinephrine

Secreted by adrenal medulla.

It stimulates glycogenolysis in liver & muscle.

It diminishes the release of insulin from pancreas.

80

Other Hormones

Anterior pituitary hormones

Growth hormone:

Elevates blood glucose level & antagonizes action of insulin.

Growth hormone is stimulated by hypoglycemia (decreases

glucose uptake in tissues)

Chronic administration of growth hormone leads to diabetes

due to B cell exhaustion.

81

SEX HORMONES

Estrogens cause increased liberation of

insulin.

Testosterone decrease blood sugar level.

82

Hyperglycemia

Thirst, dry mouth

Polyuria

Tiredness, fatigue

Blurring of vision.

Nausea, headache,

Hyperphagia

Mood change

Hypoglycemia

Sweating

Trembling,pounding heart

Anxiety, hunger

Confusion, drowsiness

Speech difficulty

Incoordination.

Inability to concentrate

83

Clinical aspects

Glycosuria: occurs when venous blood

glucose concentration exceeds

9.5-10.0mmol/L

Fructose-1,6-Biphosphatase deficiency causes

lactic acidosis & hypoglycemia..

84

Diabetes Mellitus

A multi-organ catabolic response caused by insulin insufficiency

Muscle

– Protein catabolism for gluconeogenesis

Adipose tissue

– Lipolysis for fatty acid release

Liver

– Ketogenesis from fatty acid oxidation

– Gluconeogenesis from amino acids and glycerol

Kidney

– Ketonuria and cation excretion

– Renal ammoniagenesis.

85

DENTAL ASPECTS OF CARBOHYDRATES METABOLISM

86

Role of carbohydrates in dental caries

• Fermentable carbohydrates causes loss of

caries resistance.

• Caries process is an interplay between oral

bacteria, local carbohydrates & tooth surface

Bacteria + Sugars+ Teeth Organic acids

Caries

87

Role of carbohydrates in periodontal

disease

Abnormal

glucose metabolism

Diabetes Mellitus

Periodontal disease

Excessive carbohydrate

intake

Obesity

Periodontal disease

88

RECENT CLINICAL ISSUES RELATED TO CARBOHYDRATES METABOLISM

89

Cystic Fibrosis

• CMD in Cystic Fibrosis is characterized by its high rates and

latent course.

• The patients with CMD have retarded physical development,

more pronounced morphofunctional disorders in the

bronchopulmonary system, lower lung functional parameters,

and more aggressive sputum microbial composition.

(Samoĭlenko VA et al.)

90

CMD in Gout

• OGTT causes a 34% increase in the detection rate of T2D in

patients with gout.

• Carbohydrate metabolic disturbances are revealed in the

majority of patients with gout and associated with obesity,

hypertriglyceridemia, high serum UA levels, chronic disease

forms, the high incidence of CHD and arterial

hypertension.(Eliseev MS et al.)

91

SUMMARY OF CARBOHYDRATE METABOLISM

92

PER DAY INTAKE OF CARBOHYDRATE

• Carbohydrate Calculator

http://www.calculator.net/carbohydrate-

calculator.html?ctype=metric&cage=25&csex

=f&cheightfeet=5&cheightinch=10&cpound=

160&cheightmeter=163&ckg=74&cactivity=1.

375&x=85&y=10#

93

CONCLUSION

• Carbohydrate are the measure source of energy

for the living cells. Glucose is the central

molecule in carbohydrate metabolism, actively

participating in a number of metabolic pathway.

• One component of etiology of dental caries is

carbohydrate which act as substrate for

bacteria. Every effort should be made to

reduce sugar intake for healthy tooth.

94

REFERENCES

1) Biochemistry – U.Satyanarayana-3rd Ed.

2) Textbook of Biochemistry- D.M.Vasudevan -14th Ed.

3) Textbook of Medical Biochemistry – M.N.Chattergy

– 17th Ed.

4) Text book of Physiology –Ganong – 24th Ed.

5) Text book of Oral Pathology – Shafers- 7th Ed.

6) Principles & practice of Medicine-Davidson – 21st

Ed.

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2015/1/3

• Submitted TO SIR JAVED

• Submitted by SANA DANISH

SUBAS IMTIAZ NAJAF BATOOL